Pancreatic cancer is the 4th leading cause of cancer-related deaths in the U.S. Little is known about the origin, pathogenesis, or treatment of this neoplasia. The opioid growth factor (OGF), [Met5]-enkephalin, is a native inhibitory peptide that is particularly targeted to cell proliferative events. The repressive activity of OGF on cell growth is mediated by the zeta opioid receptor. CCF is a negative growth factor in pancreatic cancer both in vitro and in vivo, Blockade of OGF action by the potent opioid antagonist naltrexone increases pancreatic cancer cell proliferation, indicating the tonic activity of OGF. Both OGF and zeta receptor are in pancreatic tumor cells. This grant hypothesizes that a native opioid peptide inhibits the growth of human pancreatic cancer, and does so through a unique opioid receptor. To test this hypothesis, we propose to: (l) Examine the cellular mechanisms of endogenous opioid action on human pancreatic tumor cell function, including DNA synthesis and the cell cycle. (2) Investigate the autocrine production of the opioid peptide related to growth of human pancreatic cancer. (3) Define the regulatory properties of opioid peptide-receptor interaction with respect to human pancreatic cancer cells. (4) Clone and sequence the zeta opioid receptor in human pancreatic neoplasia, and elucidate the function of this receptor using overexpression studies. (5) Learn about the mechanisms of endogenous opioid activity with regard to the incidence and growth of human pancreatic tumors from xenografts in nude mice. These studies will contribute to comprehending the biology of human cancer, and may provide clues to strategies for the treatment of pancreatic neoplasia. Information derived from the proposed investigation would be the first to identify a natural inhibitory substance and its receptor that serve to regulate pancreatic cancer. This research is part of a long-range program in cellular and molecular oncology which seeks to define the fundamental principles underlying pancreatic cancer in humans.